Biliverdin Reductase-A integrates insulin signaling with mitochondrial metabolism through phosphorylation of GSK3β

TL;DR

This study shows how a protein called BVR-A connects insulin signaling to brain energy metabolism, and its loss leads to insulin resistance and mitochondrial dysfunction linked to diseases like diabetes and Alzheimer's.

Contribution

The study reveals that BVR-A is essential for transporting phosphorylated GSK3β into mitochondria, linking insulin signaling to mitochondrial metabolism.

Findings

Reduced BVR-A levels disrupt insulin signaling and mitochondrial bioenergetics in the brain.

BVR-A is required to shuttle pGSK3βS9 into mitochondria, regulating oxidative phosphorylation.

Loss of BVR-A activates the mitochondrial Unfolded Protein Response (UPRmt) and mimics insulin resistance.

Abstract

Brain insulin resistance links the failure of energy metabolism with cognitive decline in both type 2 Diabetes Mellitus (T2D) and Alzheimer's disease (AD), although the molecular changes preceding overt brain insulin resistance remain unexplored. Abnormal biliverdin reductase-A (BVR-A) levels were observed in both T2D and AD and were associated with insulin resistance. Here, we demonstrate that reduced BVR-A levels alter insulin signaling and mitochondrial bioenergetics in the brain. Loss of BVR-A leads to IRS1 hyper-activation but dysregulates Akt-GSK3β complex in response to insulin, hindering the accumulation of pGSK3βS9 into the mitochondria. This event impairs oxidative phosphorylation and fosters the activation of the mitochondrial Unfolded Protein Response (UPRmt). Remarkably, we unveil that BVR-A is required to shuttle pGSK3βS9 into the mitochondria. Our data sheds light on the intricate interplay between insulin signaling and mitochondrial metabolism in the brain unraveling potential targets for mitigating the development of brain insulin resistance and neurodegeneration.

Image 1

•Insulin signaling alterations impairs mitochondrial metabolism in T2D brain.•BVR-A loss alters mitochondrial bioenergetics in the brain in response to insulin.•UPRmt is activated to face insulin signaling-mitochondria axis alterations.•BVR-A transports GSK3βS9 into the mitochondria to regulate energy metabolism.•BVR-A loss compromise the insulin response, resembling an insulin resistance state.

Insulin signaling alterations impairs mitochondrial metabolism in T2D brain.

BVR-A loss alters mitochondrial bioenergetics in the brain in response to insulin.

UPRmt is activated to face insulin signaling-mitochondria axis alterations.

BVR-A transports GSK3βS9 into the mitochondria to regulate energy metabolism.

BVR-A loss compromise the insulin response, resembling an insulin resistance state.

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